1. Field of the Invention
This invention relates to novel purine derivatives useful as non-adrenergic bronchodilators.
2. Description of the Prior Art
Theophylline, normally administered as the ethylenediamine salt (aminophylline) or choline salt, is a potent and useful non-adrenergic bronchodilator commonly prescribed for the treatment of bronchial asthma. Because it is readily soluble, aminophylline has for many years been accepted as an effective bronchodilator when given orally. Aminophylline, however, is known to have certain disadvantages, e.g. gastric irritation and cardiovascular and central nervous system side effects, which warrant a search for new non-adrenergic bronchodilators which may have more advantageous properties such as increased potency and/or reduced side effects.
With respect to the novel compounds of the present invention, a vast number of purine derivatives have been disclosed in the patent and scientific literature. Illustrative of such references are the following:
1. J. Am. Chem. Soc., 81, 197-201 (1959) discloses the synthesis of compounds having the formula ##STR4## wherein R is cyclohexyl or 2-cyclohexenyl. The compounds were prepared as potential anticancer agents. PA1 2. U.S. Pat. No. 3,917,837 discloses the use of the compound ##STR5## as an anti-inflammatory agent. 3. U.S. Pat. No. 3,930,005 discloses compounds of the formula ##STR6## wherein R.sub.2 and R.sub.3 may be inter alia hydrogen and R.sub.1 may be inter alia (lower)alkoxy. The compounds are said to possess anti-inflammatory activity. PA1 4. Belgian Pat. No. 853,086 (Farmdoc 70719Y) discloses compounds of the formula ##STR7## wherein either X is C.sub.1 -C.sub.6 alkoxy or -NHR; R is H or (lower)alkyl; Y is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.10 cycloalkyl or hydroxycycloalkyl, phenyl, halophenyl, trifluoromethyl-phenyl, bicycloalkyl or hydroxybicycloalkyl of up to 12 carbons, or -AR.sup.1 ; A is methylene or ethylene; R.sup.1 is phenyl, halophenyl, trifluoromethyl-phenyl, bicycloalkyl or hydroxybicycloalkyl of up to 12 carbons; Q is H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.10 cycloalkyl or hydroxycycloalkyl, bicycloalkyl or hydroxybicycloalkyl of up to 12 carbons, phenyl, halophenyl, trifluoromethyl-phenyl or AR.sup.1 ; or X is halogen or (lower)dialkylamino; Y is methyl, ethyl, cyclopentyl, phenyl, halophenyl, trifluoromethyl-phenyl or benzyl and Q is as previously defined. The compounds are reported to be useful in treating psoriasis. PA1 5. West German Published Application No. 2,610,985 (Farmdoc 70863Y) discloses compounds of the formula ##STR8## wherein R.sub.1 and R.sub.2 are OH or ONO.sub.2, or together form C.sub.2 -C.sub.7 alkylidene, aralkylidene or CR.sub.4 R.sub.5 ; R.sub.4 is H or C.sub.1 -C.sub.7 alkyl; R.sub.5 is OR.sub.6 or NR.sub.7 R.sub.8 ; R.sub.6 is C.sub.1 -C.sub.7 alkyl; R.sub.7 and R.sub.8 are optionally substituted C.sub.1 -C.sub.7 alkyl or C.sub.3 -C.sub.7 cycloalkyl, or together form a C.sub.2 -C.sub.5 alkylene group in which one CH.sub.2 group is optionally replaced by a heteroatom; R.sub.3 is C.sub.1 -C.sub.7 alkyl or alkoxy, optionally substituted phenyl or H; X is OR.sub.9 or NR.sub.10 R.sub.11 ; R.sub.9 is C.sub.1 -C.sub.7 alkyl, C.sub.3 -C.sub.7 cycloalkyl, optionally substituted phenyl or aralkyl; R.sub.10 and R.sub.11 are H, optionally substituted C.sub.1 -C.sub.7 alkyl, alkenyl or alkynyl, optionally substituted C.sub.3 -C.sub. 7 cycloalkyl, substituted phenyl, benzylamino, 2-methylfuryl or adamantyl, or one can be H and the other a group of the formula ##STR9## wherein n is 2-16, or R.sub.10 and R.sub.11 together form a C.sub.2 -C.sub.5 alkylene group in which one CH.sub.2 group can be replaced by a heteroatom. The compounds are said to have circulatory, cardiac and metabolic activity. PA1 6. Chem. Pharm. Bull., 23(4), 759-774 (1975) discloses inter alia compounds of the formula ##STR10## wherein R is (lower)alkyl. The compounds are said to have coronary vasodilating activity. PA1 7. Japanese Published Application 52-71492 (Farmdoc 53190Y) discloses compounds of the formula ##STR11## wherein R.sub.1 is C.sub.1 -C.sub.10 straight or branched alkyl, C.sub.5 -C.sub.10 cycloalkyl, C.sub.7 -C.sub.11 aralkyl or piperazinoethyl of the formula ##STR12## wherein R.sub.2 is C.sub.7 -C.sub.11 aralkyl, mono-substituted aralkyl, cinnamyl or fluorenyl; R.sub.3 is C.sub.1 -C.sub.10 straight or branched alkyl, C.sub.5 -C.sub.10 cycloalkyl, C.sub.7 -C.sub.11 aralkyl or piperazinoethyl as defined above, with the exclusion of compounds in which R.sub.1 and R.sub.3 are methyl, R.sub.1 is methyl and R.sub.3 is ethyl and R.sub.1 is C.sub.5 -C.sub.10 cycloalkyl and R.sub.3 is C.sub.1 -C.sub.4 alkyl, C.sub.5 -C.sub.10 cycloalkyl or C.sub.7 -C.sub.11 aralkyl. The compounds are reported to show an inhibitory effect on blood platelet aggregation and to have coronary dilating activity. PA1 8. Chem Pharm. Bull., 25(7), 1811-1821 (1977) discloses preparation of 2-thioadenosine derivatives including inter alia a compound of the formula ##STR13## The above compound is reported to be slightly effective as a platelet aggregation inhibitor. The authors note that the corresponding compound having a ribose sugar moiety at the 9-position was far more effective and conclude that the ribosyl moiety of 2-thioadenosine derivatives is essential for effective inhibition of platelet aggregation and cannot be replaced by other substituents. PA1 (1) reacting 2,6-dichloropurine with about one equivalent of HgCl.sub.2 or a source of Na.sup.+, K.sup.+, Tl.sup.+ or Ag.sup.+ (i.e. a salt which dissociates to form the desired ion) in an inert solvent to produce a metal derivative having the formula ##STR18## wherein M is HgCl, Na, K, Tl or Ag; (2) condensing metal derivative III in a substantially anhydrous inert organic solvent with a 3-halocyclohexene of the formula ##STR19## wherein X is chloro, bromo or iodo to produce an intermediate having the formula ##STR20## (3) subjecting intermediate V to amination with NH.sub.3 in an inert solvent to produce an intermediate having the formula ##STR21## (4) heating intermediate II with an alkali metal alkoxide of the formula RO-alk wherein alk represents sodium or potassium and R is as defined above in an inert solvent to produce the desired free base product of formula I and, if desired, converting said product by methods known per se to a pharmaceutically acceptable acid addition salt thereof. PA1 (1) reacting 2,6-dichloropurine with about one equivalent of HgCl.sub.2 or a source of Na.sup.+, K.sup.+, Tl.sup.+, or Ag.sup.+ in an inert solvent to produce metal derivative III; PA1 (2) condensing metal derivative III in a substantially anhydrous inert organic solvent with a cyclohexyl halide of the formula ##STR23## wherein X is chloro, bromo or iodo to produce an intermediate having the formula ##STR24## (3) subjecting intermediate V' to amination with NH.sub.3 in an inert solvent to produce an intermediate having the formula ##STR25## (4) heating intermediate II' with an alkali metal alkoxide of the formula RO-alk wherein alk represents sodium or potassium and R is as defined above in an inert solvent to produce the desired free base product of formula I and, if desired, converting said product by methods known per se to a pharmaceutically acceptable acid addition salt thereof.
No references have been found disclosing 2,9-disubstituted adenine derivatives having an alkoxy substituent as the 2-position and a cycloalkyl or cycloalkenyl group at the 9-position.